EP1042326B1 - Nouveaux derives de l'acronycine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent - Google Patents

Nouveaux derives de l'acronycine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent Download PDF

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EP1042326B1
EP1042326B1 EP98962511A EP98962511A EP1042326B1 EP 1042326 B1 EP1042326 B1 EP 1042326B1 EP 98962511 A EP98962511 A EP 98962511A EP 98962511 A EP98962511 A EP 98962511A EP 1042326 B1 EP1042326 B1 EP 1042326B1
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EP1042326A1 (fr
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Michel Koch
François Tillequin
Sylvie Michel
Ghanem Atassi
Alain Pierre
Bruno Pfeiffer
Pierre Renard
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Laboratoires Servier SAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems

Definitions

  • the present invention relates to new acronycin derivatives, their process for preparation and pharmaceutical compositions containing them.
  • Acronycin is an alkaloid with anti-tumor properties demonstrated in experimental models ( J. Pharmacol. Sci. 1966, 55 (8), 758-768). However, despite a broad spectrum of activity, the low solubility of acronycin limits its bioavailability and does not make it possible to envisage its use in a mode of administration of the injectable type.
  • the compounds of the invention in addition to the fact that they are new, have properties of interesting solubilization and adapted to an administration of the products in forms liquids and also surprisingly exhibit in-vitro and in-vivo activity very higher than those observed so far.
  • the new analogues, discovered by the Applicant thus have anti-tumor properties which make them particularly suitable for use in the treatment of cancers and in particular tumors solid.
  • hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic acids, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane sulfonic, camphoric, etc ...
  • non-limiting examples that may be mentioned sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.
  • R 3 and R 4 preferred according to the invention are the linear or branched (C 1 -C 6 ) alkyl groups, with R 3 and R 4 identical or different.
  • the preferred substituents R 2 according to the invention are the linear or branched (C 1 -C 6 ) alkoxy groups, or the amino groups optionally substituted by one or two substituents as defined above, and advantageously the amino groups substituted by a group of formula -R 9 -NR 7 R 8 with R 9 is as defined above, and R 7 , R 8 , identical or different, represent a hydrogen atom or a linear or branched (C 1 -C 6 ) alkyl group.
  • optical isomers, N-oxides, as well as, where appropriate, the addition salts with an acid or with a base, pharmaceutically acceptable, preferred compounds are an integral part of the invention.
  • the compounds of formula (II), (III), (VI) and (VII) are either commercial compounds or are obtained according to conventional methods of organic synthesis and for the compounds of formula (VII) are obtained according to the conditions described in Chem. Ber . 1978, 191, 439.
  • the condensation reaction between the compounds of formula (VI) and the compounds of formula (VII) is described in particular in the review Heterocycles, 1992, 34 (4), 799-806.
  • the compounds of formula (I) exhibit particularly anti-tumor properties interesting. They have excellent in vitro cytotoxicity on cell lines, and a action on the cell cycle, and are active in vivo. In addition, these new compounds have shown to be much more active and potent than the reference compound, acronycin. They have, in addition, the property of being soluble, thus allowing administration by intravenous. The characteristic properties of these compounds allow their use in therapeutic as anti-tumor agents.
  • the present invention also relates to pharmaceutical compositions containing as active ingredient at least one compound of formula (I), its optical isomers, N-oxides or one of its addition salts with a base or a pharmaceutically acceptable acid, alone or in combination with one or more inert, non-toxic excipients or vehicles, pharmaceutically acceptable.
  • compositions according to the invention it will be cited more particularly those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per or transcutaneous, nasal, rectal, perlingual, ocular or respiratory, and in particular simple or coated tablets, tablets sublingual, capsules, capsules, suppositories, creams, ointments, gels dermal, injectable or drinkable preparations, aerosols, eye drops or nasal, etc ...
  • the useful dosage varies according to the age and weight of the patient, the route of administration, the nature and the severity of the condition and the taking of any associated treatments and ranges from 0.5 mg to 500 mg in one or more doses per day.
  • the starting materials used are known products or prepared according to methods known operating procedures.
  • Example 1 6-Hydroxy-3,3-dimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7-one.
  • Example 4 0.33 g of the product of Example 4 is added to a cooled solution of 0.82 ml of pyridine and 0.82 ml of acetic anhydride. After 6 days at room temperature, the reaction medium is poured onto ice. . A precipitate is formed which is filtered, washed with water and then dried under vacuum. 0.36 g of the expected product is obtained. Melting point: 163 ° C.
  • Example 7 cis -7-Methoxy-4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5': 4.5] pyrano [3,2-h] acridin-2,8-dione
  • Example 8 6- (Dimethylaminoethylamino) -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7-one
  • Example 11 6 - [(3-Morpholine-4-yl) propylaminol-3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7-one
  • Example 12 6 - [(2-Morpholine-4-yl) ethylamino] -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7- one
  • Example 13 6 - [(2-Piperidine-1-yl) ethylamino] -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7- one
  • Example 4 The procedure is as in Example 4, using the compound of Example 8 as the substrate.
  • Example 16 ( ⁇ ) - cis -9-Methoxy-6,6,17-trimethyl-3,4,5a, 10,17,17c-hexahydro-2H, 6H-benzo [b] [1,4] dioxepino [ 2 ', 3': 4,5] pyrano [3,2-h] acridin-2,4,10-trione
  • Example 5 The procedure is as in Example 5, using the compound of Example 4 as the substrate. and as a reagent acylmalonic dichloride.
  • Example 17 cis -7- (Dimethylaminoethylamino) -4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5': 4, 5] pyrano [3,2-h] acridin-2,8-dione
  • Example 21 ( ⁇ ) - cis -1-Acetoxy-2-benzoyloxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2 -h] acridin-7-one.
  • Step 1 ( ⁇ ) -1-Azido-2-hydroxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h ] acridin-7-one
  • Step 2 ( ⁇ ) -1-Amino-2-hydroxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h ] acridin-7-one.
  • Example 23 7-Methoxy-4,4,15-trimethyl-1,3a, 4,8,15,15c-hexahydro-2H-benzo [b] [1,3] oxazolo [4 ', 5': 4, 5] pyrano [3,2-h] acridine-2,8-dione
  • Example 28 6 - [(2-Morpholine-4-yl) ethyloxy] -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7- one
  • Example 31 6 - [(Carbomethoxy) propylamino] -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7-one
  • Example 32 6 - [(Carbomethoxy) butylamino] -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7-one
  • Example 33 cis -6- (Dimethylaminopropylamino) -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
  • Example 4 The procedure is as in Example 4, using the compound of Example 9 as the substrate.
  • Example 34 cis -6 - [(2-Morpholin-4-yl) ethylamino] -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin-7-one
  • Example 35 cis -6 - [(2-Piperidin-1-yl) ethylamino] -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin-7-one
  • Example 36 trans -6- (Dimethylaminoethylamino) -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
  • Example 37 cis -6- (Dimethylaminoethyloxy) -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
  • Example 38 cis -6- (Dimethylaminopropyloxy) -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
  • Example 39 cis- 6 - [(2-Morpholine-4-yl) ethyloxy] -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin-7-one
  • Example 40 cis -6 - [(Carbomethoxy) methylamino] -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2- h] acridin-7-one
  • Example 41 cis -6 - [(Carbomethoxy) propylamino] -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2- h] acridin-7-one
  • Example 42 cis -1,2-Diacetoxy-6- (dimethylaminopropylamino) -3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
  • Example 43 cis -1,2-Diacetoxy-6 - [(2-morpholine-4-yl) ethylamino] -3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin-7-one
  • Example 46 cis -1,2-Diacetoxy-6- (dimethylaminoethyloxy) -3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
  • Example 47 cis -1,2-Diacetoxy-6- (dimethylaminopropyloxy) -3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
  • Example 48 cis -1,2-Diacetoxy-6 - [(carbomethoxy) methylamino] -3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2- h] acridin-7-one
  • Example 49 cis -1,2-Diacetoxy-6 [(carbomethoxy) propylamino] -3,3,14-trimethyl-2,3,7,14-tetrahdyro-1H-benzo [b] pyrano [3,2-h ] acridin-7-one
  • Example 50 cis -7- (Dimethylaminopropylamino) -4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo- [4 ', 5': 4 , 5] pyrano [3,2-h] acridin-2,8 -dione
  • Example 51 cis -6 - [(2-Morpholine-4-yl) ethylamino] -4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5': 4.5] pyrano [3,2-h] acridin-2,8 -dione
  • Example 52 cis -6 - [(2-Piperidine-1-yl) ethylamino] -4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5': 4,5] pyrano [3,2-h] acridin-2,8-dione
  • Example 53 cis -6- (Dimethylaminoethyloxy) -4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5': 4, 5] pyrano [3,2-h] acridin-2,8-dione
  • Example 54 cis -6 - [(Carbomethoxy) propylamino] -4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5' : 4,5] pyrano [3,2-h] acridin-2,8-dione
  • Example 55 cis -7-Methoxy-4,4,15-trimethyl-2-thioxo-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5': 4,5] pyrano [3,2-h] acridin-8-one
  • Example 56 cis -7- (Dimethylaminoethylamino) -4,4,15-trimethyl-2-thioxo-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5 ': 4,5] pyrano [3,2-h] acridin-8-one
  • Example 55 The procedure is as in Example 55 using as substrate in the first step the composed of example 15.
  • the product is isolated by chromatography on silica gel from Example 22 where it is forms as a co-product during the synthesis of this compound.
  • Example 58 7-Methoxy-4,4,15-trimethyl-1,2,3,3a, 4,8,15,15c-octahydro-benzo [b] imidazo [4 ', 5': 4,5] pyrano [3,2-h] acridin-2,8-dione
  • Example 57 The compound of Example 57 is treated according to the conditions described in Tetrahedron. Lett. 1974, 1191.
  • Example 60 9-Methoxy-6,6,17-trimethyl-1,3,4,5a, 6,10,17,17c-octahydro-2H-benzo [b] [1,4] oxazepino [3 ', 2 ': 4,5] pyrano [3,2-h] acridin-2,4,10-trione
  • Example 2 The procedure is as in Example 2, using the compound of Example 61.
  • Example 63 cis -10.11-Dichloro-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2 -h] acridin-7-one
  • Example 4 The procedure is as in Example 4, using the compound of Example 62.
  • Example 2 The procedure is as in Example 2, using the compound of Example 66.
  • Example 68 cis -10,11-Di -tert -butyl-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin-7-one
  • Example 4 The procedure is as in Example 4, using the compound of Example 67.
  • Example 69 cis -1,2-Diacetoxy-10,11 - di- tert -butyl-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin-7-one
  • Example 5 The procedure is as in Example 5, using the compound of Example 68.
  • Example 70 10,11-Di- tert -butyl-6- (dimethylaminoethylamino) -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7 -one
  • Example 8 The procedure is as in Example 8, using the compound of Example 67.
  • Murine leukemia L1210 has been used in vitro.
  • the cells are cultured in complete RPMI 1640 culture medium containing 10% of fetal calf serum, 2 mM of glutamine, 50 U / ml of penicillin, 50 ⁇ g / ml of streptomycin and 10 mM of Hepes, pH: 7, 4.
  • the cells are distributed in microplates and exposed to cytotoxic compounds for 4 doubling times, ie 48 hours. The number of viable cells is then quantified by a colorimetric test, the Microculture Tetrazolium Assay (J. Carmichael et al., Cancer Res., 47 , 936-942, (1987)).
  • IC 50 a concentration of cytotoxic agent which inhibits the proliferation of the treated cells by 50%.
  • Table 1 Cytotoxicity for L 1210 cells in culture products Cytotoxicity IC 50 ( ⁇ M) Example 7 0,023 acronycine 27.0
  • the P 388 line (murine leukemia) was supplied by the National Cancer Institute (Frederick, USA).
  • the tumor cells (10 6 cells) were inoculated on day 0 in the peritoneal cavity of female B6D2F1 mice (Iffa Credo, France).
  • Six mice weighing 18 to 20 g were used per experimental group.
  • the products were administered intraperitoneally on day 1.
  • Table 2 indicates the antitumor activity obtained at the optimal doses. Antitumor activity on the P 388 line Product Diagram way Optimal dose (mg / kg) T / C% Example 7 J1 ip 12.5 327 acronycine J1 ip 200 125
  • Example 7 The product of Example 7 is very active in this model, whereas acronycin is only marginally active.
  • the HT29 line was supplied by the ATCC (American Type Culture Collection, Rockville, USA).
  • the tumor cells were inoculated into female Nude Swiss mice (10 7 cells per animal) subcutaneously. The tumors were then removed, dissociated into fragments which were grafted onto Nude mice subcutaneously. When the tumor volume reached 50 to 100 mm 3 , the mice were divided into experimental groups comprising 8 (control group) or 6 (treated groups) animals (day 0). The products were administered iv once a week for 3 weeks.
  • V0 and Vt being respectively the initial volume and the volume at the measurement time t.
  • Table 3 indicates the antitumor activity obtained at the optimal doses for Example 5: Antitumor activity on the HT29 line Product Diagram way Optimal Dose (mg / kg) T / C% at day 32 Example 5 D0, 7.14 iv 3.12 17
  • Example 5 inhibits the growth of the HT29 tumor, which is general, not very sensitive to anti-tumor agents. This product is very active in this model, the inhibition being 83% on day 32, ie 18 days after the last administration.
  • Preparation formula for 1000 tablets dosed at 10 mg Composed of Example 7 10 g Lactose 40 g Magnesium stearate 10 g Wheat starch 15g Corn starch 15g Silica 3 g hydroxypropyl 5 g

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EP98962511A 1997-12-19 1998-12-18 Nouveaux derives de l'acronycine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent Expired - Lifetime EP1042326B1 (fr)

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FR9716131A FR2772765B1 (fr) 1997-12-19 1997-12-19 Nouveaux derives de l'acronycine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR9716131 1997-12-19
PCT/FR1998/002785 WO1999032491A1 (fr) 1997-12-19 1998-12-18 Nouveaux derives de l'acronycine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

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FR2795071B1 (fr) * 1999-06-16 2001-07-27 Adir Nouveaux derives de carboxylate de 7-oxo-2,3,7,14- tetrahydro-1h-benzo[b]pyrano[3,2,h] acridine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US7056929B2 (en) * 2001-07-25 2006-06-06 Les Laboratoires Servier Benzo[b]pyrano[3,2-h]acridin-7-one compounds
FR2827864B1 (fr) * 2001-07-25 2005-09-16 Servier Lab Nouveaux derives de benzo[b]pyrano[3,2-h]acridin-7-one, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2856687B1 (fr) * 2003-06-25 2005-09-16 Servier Lab Nouveaux derives de benzo[a]pyrano[3,2-h]acridin-7-one, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2865734B1 (fr) * 2004-02-03 2006-05-19 Servier Lab NOUVAEUX DERIVES DE BENZO[b]CHROMENO-NAPHTHYRIDIN-7-ONE ET DE PYRANO[2'3':7,8]QUINO[2,3-b]QUINOXALIN-7-ONE, LEUR PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES QUI LES CONTIENNENT
FR2879600B1 (fr) * 2004-12-22 2007-02-09 Servier Lab Nouveaux derives cinnamates de benzo[b]pyrano[3,2-h]acridin-7-one, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
JP4392502B2 (ja) * 2005-06-10 2010-01-06 国立大学法人 岡山大学 蛍光性アミノ酸誘導体
US11784731B2 (en) * 2021-03-09 2023-10-10 Apple Inc. Multi-phase-level signaling to improve data bandwidth over lossy channels
WO2024081561A2 (en) * 2022-10-13 2024-04-18 Siemens Healthcare Diagnostics Inc. Acridinium compounds with fused heterocycles

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CA2315909A1 (fr) 1999-07-01
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PT1042326E (pt) 2002-10-31
FR2772765B1 (fr) 2000-03-17
AU1766399A (en) 1999-07-12
CN1109686C (zh) 2003-05-28
ATE219491T1 (de) 2002-07-15
CN1282332A (zh) 2001-01-31
HUP0100342A2 (hu) 2001-09-28
HK1033131A1 (en) 2001-08-17
CA2315909C (fr) 2007-01-02
US6288073B1 (en) 2001-09-11
EP1042326A1 (fr) 2000-10-11
JP3825630B2 (ja) 2006-09-27
ES2179548T3 (es) 2003-01-16
BR9813756A (pt) 2000-10-03
HUP0100342A3 (en) 2003-04-28
WO1999032491A1 (fr) 1999-07-01
ZA9811645B (en) 1999-06-24
NO20003106D0 (no) 2000-06-16
DE69806189D1 (de) 2002-07-25
NZ504833A (en) 2001-11-30
AU738322B2 (en) 2001-09-13
FR2772765A1 (fr) 1999-06-25
NO20003106L (no) 2000-08-16
DK1042326T3 (da) 2002-09-23
DE69806189T2 (de) 2003-02-13
JP2001526290A (ja) 2001-12-18

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